Long-acting muscarinic receptor antagonists for the treatment of respiratory disease

Pulmonary Pharmacology and Therapeutics

Volumn 26, Issue 3, 2013, Pages 307-317

  Cazzola, Mario ^a,b   Page, Clive ^c   Matera, Maria Gabriella ^d  

^a UNIVERSITY OF ROME TOR VERGATA   (Italy)

^b IRCCS SAN RAFFAELE PISANA   (Italy)

^c KING'S COLLEGE LONDON   (United Kingdom)

^d SECOND UNIVERSITY OF NAPLES   (Italy)

Author keywords

Anticholinergic; COPD; LAMA; Novel

Indexed keywords

ACLIDINIUM BROMIDE; AZD 8683; BETA 2 ADRENERGIC RECEPTOR STIMULATING AGENT; CHF 5259; CHF 5407; EP 101; FORMOTEROL; GLUCOCORTICOID; GLYCOPYRRONIUM BROMIDE; GP MDI; INDACATEROL; IPRATROPIUM BROMIDE; MUSCARINIC RECEPTOR BLOCKING AGENT; OLODATEROL; OXITROPIUM BROMIDE; TD 4208; TIOTROPIUM BROMIDE; UMECLIDINIUM; UNCLASSIFIED DRUG; V 0162; VILANTEROL;

ASTHMA; CHRONIC OBSTRUCTIVE LUNG DISEASE; DRUG ACTIVITY; HUMAN; PRIORITY JOURNAL; RESPIRATORY TRACT DISEASE; REVIEW;

ADMINISTRATION, INHALATION; ADRENERGIC BETA-2 RECEPTOR AGONISTS; ASTHMA; CLINICAL TRIALS AS TOPIC; DELAYED-ACTION PREPARATIONS; DRUG COMBINATIONS; DRUG THERAPY, COMBINATION; GLUCOCORTICOIDS; HUMANS; MUSCARINIC ANTAGONISTS; NEBULIZERS AND VAPORIZERS; QUALITY OF LIFE;

EID: 84875959946     PISSN: 10945539     EISSN: 15229629     Source Type: Journal    
DOI: 10.1016/j.pupt.2012.12.006     Document Type: Review

References (106)

1. Barnes P.J., Shapiro S.D., Pauwels R.A. Chronic obstructive pulmonary disease: molecular and cellular mechanisms. Eur Respir J 2003, 22:672-688.
2. Hogg J.C. Chronic obstructive pulmonary disease: an overview of pathology and pathogenesis. Novartis Found Symp 2001, 234:4-19.
3. Canning B.J. Reflex regulation of airway smooth muscle tone. J Appl Physiol 2006, 101:971-985.
4. National Clinical Guideline Centre Chronic obstructive pulmonary disease: management of chronic obstructive pulmonary disease in adults in primary and secondary care 2010, [Internet], [cited 2012 April 27]. Available from:. http://guidance.nice.org.uk/CG101/Guidance/pdf/English.
5. National Institute for Health and Clinical Excellence Inhaled corticosteroids for the treatment of chronic asthma in adults and children aged 12 years and over 2008, [Internet], [cited 2012 April 27]. Available from:. http://www.nice.org.uk/nicemedia/pdf/TA138Guidance.pdf.
6. Global Initiative for Asthma Global Initiative for Asthma 2011, [Internet], [cited 2012 October 17]. Available from:. http://www.ginasthma.org.
7. Barnes P.J. Rationale for the use of antimuscarinics in obstructive airway disease. Rev Contemp Pharmacother 1992, 3:173-182.
8. Gwilt C.R., Donnelly L.E., Rogers D.F. The non-neuronal cholinergic system in the airways: an unappreciated regulatory role in pulmonary inflammation?. Pharmacol Ther 2007, 115:208-222.
9. Moffatt J.D., Cocks T.M., Page C.P. Role of the epithelium and acetylcholine in mediating the contraction to 5-hydroxytryptamine in the mouse isolated trachea. Br J Pharmacol 2004, 141:1159-1166.
10. Barnes P.J. Muscarinic receptor subtypes in airways. Life Sci 1993, 52:521-527.
11. Roffel A.F., Meurs H., Zaagsma J. Identification, localization and function of muscarinic receptor subtypes in airways. Muscarinic receptors in airways diseases 2001, 63-85. Birkhäuser Verlag, Basel, Switzerland. J. Zaagsma, H. Meurs, A.F. Roffel (Eds.).
12. Wess J., Eglen R.M., Gautam D. Muscarinic acetylcholine receptors: mutant mice provide new insights for drug development. Nat Rev Drug Discov 2007, 6:721-733.
13. Scullion J.E. The development of anticholinergics in the management of COPD. Int J Chron Obstruct Pulmon Dis 2007, 2:33-40.
14. Matera M.G., Page C.P., Cazzola M. Novel bronchodilators for the treatment of chronic obstructive pulmonary disease. Trends Pharmacol Sci 2011, 32:495-506.
15. Peters S.P., Kunselman S.J., Icitovic N., Moore W.C., Pascual R., Ameredes B.T., et al. Tiotropium bromide step-up therapy for adults with uncontrolled asthma. N Engl J Med 2010, 363:1715-1726.
16. Bateman E.D., Kornmann O., Schmidt P., Pivovarova A., Engel M., Fabbri L.M. Tiotropium is noninferior to salmeterol in maintaining improved lung function in B16-Arg/Arg patients with asthma. J Allergy Clin Immunol 2011, 128:315-322.
17. Magnussen H., Bugnas B., van Noord J., Schmidt P., Gerken F., Kesten S. Improvements with tiotropium in COPD patients with concomitant asthma. Respir Med 2008, 102:50-56.
18. Casaburi R., Mahler D.A., Jones P.W., Wanner A., San P.G., ZuWallack R.L., et al. A long-term evaluation of once-daily inhaled tiotropium in chronic obstructive pulmonary disease. Eur Respir J 2002, 19:217-224.
19. Vincken W., van Noord J.A., Greefhorst A.P., Bantje T.A., Kesten S., Korducki L., et al. Improved health outcomes in patients with COPD during 1 yr's treatment with tiotropium. Eur Respir J 2002, 19:209-216.
20. van Noord J.A., Smeets J.J., Custers F.L.J., Korducki L., Cornelissen P.J.G. Pharmacodynamic steady state of tiotropium in patients with chronic obstructive pulmonary disease. Eur Respir J 2002, 19:639-644.
21. ® 18 microgram, inhalation powder, hard capsule. Summary of product characteristics 2012, [Internet], [cited 2012 July 5]. Available from:. http://www.medicines.org.uk/emc/medicine/10039.
22. Tobin G., Ryberg A.T., Gentle S., Edwards A.V. Distribution and function of muscarinic receptor subtypes in the ovine submandibular gland. J Appl Physiol 2006, 100:1215-1223.
23. Calverley P.M. COPD: what is the unmet need?. Br J Pharmacol 2008, 155:487-493.
24. Agusti A., Hedner J., Marin J.M., Barbe F., Cazzola M., Rennard S. Night-time symptoms: a forgotten dimension of COPD. Eur Respir Rev 2011, 20:183-194.
25. Partridge M.R., Karlsson N., Small I.R. Patient insight into the impact of chronic obstructive pulmonary disease in the morning: an internet survey. Curr Med Res Opin 2009, 25:2043-2048.
26. Kessler R., Partridge M.R., Miravitlles M., Cazzola M., Vogelmeier C., Leynaud D., et al. Symptom variability in patients with severe COPD: a pan-European cross-sectional study. Eur Respir J 2011, 37:264-272.
27. Singh S., Loke Y.K., Furberg C.D. Inhaled anticholinergics and risk of major adverse cardiovascular events in patients with chronic obstructive pulmonary disease: a systematic review and meta-analysis. JAMA 2008, 300:1439-1450.
28. Brodde O.E., Michel M.C. Adrenergic and muscarinic receptors in the human heart. Pharmacol Rev 1999, 51:651-690.
29. Disse B., Reichl R., Speck G., Traunecker W., Ludwig Rominger K.L., Hammer R. Ba 679 BR, a novel long-acting anticholinergic bronchodilator. Life Sci 1993, 52:537-544.
30. Gavaldà A., Miralpeix M., Ramos I., Otal R., Carreño C., Viñals M., et al. Characterization of aclidinium bromide, a novel inhaled muscarinic antagonist, with long duration of action and a favorable pharmacological profile. J Pharmacol Exp Ther 2009, 331:740-751.
31. Casarosa P., Bouyssou T., Germeyer S., Schnapp A., Gantner F., Pieper M. Preclinical evaluation of long-acting muscarinic antagonists: comparison of tiotropium and investigational drugs. J Pharmacol Exp Ther 2009, 330:660-668.
32. Villetti G., Pastore F., Bergamaschi M., Bassani F., Bolzoni P.T., Battipaglia L., et al. Bronchodilator activity of (3R)-3-[[[(3-fluorophenyl)[(3,4,5-trifluorophenyl)methyl]amino] carbonyl]oxy]-1-[2-oxo-2-(2-thienyl)ethyl]-1-azoniabicyclo[2.2.2]octane bromide (CHF5407), a potent, long-acting, and selective muscarinic M3 receptor antagonist. J Pharmacol Exp Ther 2010, 335:622-635.
33. Singh S., Loke Y.K., Enright P.L., Furberg C.D. Mortality associated with tiotropium mist inhaler in patients with chronic obstructive pulmonary disease: systematic review and meta-analysis of randomised controlled trials. BMJ 2011, 342:d3215.
34. Tashkin D.P., Celli B., Senn S., Burkhart D., Kesten S., Menjoge S., et al. A 4-year trial of tiotropium in chronic obstructive pulmonary disease. N Engl J Med 2008, 359:1543-1554.
35. Newman S.P. Use of gamma scintigraphy to evaluate the performance of new inhalers. J Aerosol Med 1999, 12(Suppl. 1):S25-S31.
36. Newman S.P., Brown J., Steed K.P., Reader S.J., Kladders H. Lung deposition of fenoterol and flunisolide delivered using a novel device for inhaled medicines: comparison of RESPIMAT with conventional metered-dose inhalers with and without spacer devices. Chest 1998, 113:957-963.
37. Pitcairn G., Reader S., Pavia D., Newman S. Deposition of corticosteroid aerosol in the human lung by Respimat Soft Mist inhaler compared to deposition by metered dose inhaler or by turbuhaler dry powder inhaler. J Aerosol Med 2005, 18:264-272.
38. Caillaud D., Le Merre C., Martinat Y., Aguilaniu B., Pavia D. A dose-ranging study of tiotropium delivered via Respimat Soft Mist Inhaler or HandiHaler in COPD patients. Int J Chron Obstruct Pulmon Dis 2007, 2:559-565.
39. Alberti J., Martinet A., Sentellas S., Salva M. Identification of the human enzymes responsible for the enzymatic hydrolysis of aclidinium bromide. Drug Metab Dispos 2010, 38:1202-1210.
40. Sentellas S., Ramos I., Alberti J., Salva M., Anton F., Miralpeix M., et al. Aclidinium bromide, a new, long-acting, inhaled muscarinic antagonist: in vitro plasma inactivation and pharmacological activity of its main metabolites. Eur J Pharm Sci 2010, 39:283-290.
41. Chanez P., Burge P.S., Dahl R., Creemers J., Chuchalin A., Lamarca R., et al. Aclidinium bromide provides long-acting bronchodilation in patients with COPD. Pulm Pharmacol Ther 2010, 23:15-21.
42. Joos G.F., Schelfhout V.J., Pauwels R.A., Kanniess F., Magnussen H., Lamarca R., et al. Bronchodilatory effects of aclidinium bromide, a long-acting muscarinic antagonist, in COPD patients. Respir Med 2010, 104:865-872.
43. Jones P.W., Rennard S.I., Agusti A., Chanez P., Magnussen H., Fabbri L., et al. Efficacy and safety of once-daily aclidinium in chronic obstructive pulmonary disease. Respir Res 2011, 12:55.
44. Donohue J.F. Minimal clinically important differences in COPD lung function. COPD 2005, 2:111-124.
45. Mahler D.A., Witek T.J. The MCID of the transition dyspnea index is a total score of one unit. COPD 2005, 2:99-103.
46. Fuhr R., Magnussen H., Sarem K., Llovera A.R., Kirsten A.M., Falques M., et al. Efficacy of aclidinium bromide 400 mg twice daily compared with placebo and tiotropium in patients with moderate to severe COPD. Chest 2012, 141:745-752.
47. Jones P.W., Singh D., Bateman E.D., Agusti A., Lamarca R., de Miquel G., et al. Efficacy and safety of twice-daily aclidinium bromide in COPD patients: the ATTAIN study. Eur Respir J 2012, 40:830-836.
48. Kerwin E.M., D'Urzo A.D., Gelb A.F., Lakkis H., Garcia Gil E., Caracta C.F., et al. Efficacy and safety of a 12-week treatment with twice-daily aclidinium bromide in COPD patients (ACCORD COPD I). COPD 2012, 9:90-101.
49. Agusti A., Jones P.W., Bateman E.D., Singh D., Lamarca R., de Miquel G., et al. Improvement in symptoms and rescue medication use with aclidinium bromide in patients with chronic obstructive pulmonary disease: results from ATTAIN. Eur Respir J 2011, 38(Suppl. 55):149s.
50. Gelb A.F., Make B.J., Tashkin D.P., Zhong X., Garcia Gil E., Caracta C. Long-term efficacy and safety of twice-daily aclidinium bromide in COPD patients: a one-year study. Am J Respir Crit Care Med 2012, 185:A2256.
51. D'Urzo A.D., Kerwin E.M., Donohue J.F., Rennard S.I., Gelb A.F., Lakkis H., et al. Long-term extension study of ACCORD COPD I: effects of two doses of twice-daily aclidinium bromide in COPD patients. Am J Respir Crit Care Med 2012, 185:A2913.
52. Madueno A., Martin A., Peculo J.A., Anton E., Paravisini A., Leon A. Usefulness of inspiratory capacity measurement in COPD patients in the primary care setting. Int J Gen Med 2009, 2:219-225.
53. O'Donnell D.E., Fluge T., Gerken F., Hamilton A., Webb K., Aguilaniu B., et al. Effects of tiotropium on lung hyperinflation, dyspnoea and exercise tolerance in COPD. Eur Respir J 2004, 23:832-840.
54. Diaz O., Villafranca C., Ghezzo H., Borzone G., Leiva A., Milic-Emil J., et al. Role of inspiratory capacity on exercise tolerance in COPD patients with and without tidal expiratory flow limitation at rest. Eur Respir J 2000, 16:269-275.
55. O'Donnell D.E., Revill S.M., Webb K.A. Dynamic hyperinflation and exercise intolerance in chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2001, 164:770-777.
56. Maltais F., Celli B., Casaburi R., Porszasz J., Jarreta D., Seoane B., et al. Aclidinium bromide improves exercise endurance and lung hyperinflation in patients with moderate to severe COPD. Respir Med 2011, 105:580-587.
57. Jansat J.M., Lamarca R., Garcia Gil E., Ferrer P. Safety and pharmacokinetics of single doses of aclidinium bromide, a novel long-acting, inhaled antimuscarinic, in healthy subjects. Int J Clin Pharmacol Ther 2009, 47:460-468.
58. Jansat J.M., Lamarca R., de Miquel G., Schrodter A., Miletzki B., Gurniak M. Safety and pharmacokinetics of multiple doses of aclidinium bromide, a novel long-acting muscarinic antagonist for the treatment of chronic obstructive pulmonary disease, in healthy participants. J Clin Pharmacol 2009, 49:1239-1246.
59. Lasseter K.C., Dilzer S., Jansat J.M., Garcia Gil E., Caracta C., Ortiz S. Safety and pharmacokinetics of multiple doses of aclidinium bromide administered twice daily in healthy volunteers. Pulm Pharm Ther 2012, 25:193-199.
60. Schmid K., Pascual S., Garcia Gil E., Ortiz S., Jansat J.M. Pharmacokinetics and safety of aclidinium bromide, a muscarinic antagonist, in adults with normal or impaired renal function: a phase I, open-label, single-dose clinical trial. Clin Ther 2010, 32:1798-1812.
61. de la Motte S., Beier J., Schmid K., Pascual S., Jansat J.M., Garcia Gil E. Pharmacokinetics and safety of aclidinium bromide in younger and elderly patients with chronic obstructive pulmonary disease. Int J Clin Pharmacol Ther 2012, 50:403-412.
62. Lasseter K.C., Aubets J., Chuecos F., Garcia Gil E. Aclidinium bromide, a long-acting antimuscarinic, does not affect QT interval in healthy subjects. J Clin Pharmacol 2010, 51:923-932.
63. ® inhaler: a novel, multidose dry powder inhaler. Int J Clin Pract 2012, 66:309-317.
64. Greguletz R., Fyrnys B., Goede J., Haaije de Boer A., Frijlink H.W. A novel multidose dry powder inhaler demonstrates consistent aerodynamic features. Am J Respir Crit Care Med 2009, 179:A4578.
65. ®. Eur Respir J 2011, 38(Suppl. 55):3979.
66. Haddad E.B., Patel H., Keeling J.E., Yacoub M.H., Barnes P.J., Belvisi M.G. Pharmacological characterization of the muscarinic receptor antagonist, glycopyrrolate, in human and guinea-pig airways. Br J Pharmacol 1999, 127:413-420.
67. Ramos I., Beleta J., Vilella D., Gomez-Angelats M., Aparici M., Calama E., et al. Muscarinic receptor selectivity of aclidinium bromide and glycopyrrolate in vitro. Eur Respir J 2010, 36(Suppl. 54):219s.
68. Otal R., Gavalda A., Llupia J., Beleta J., Miralpeix M. In vivo aclidinium bromide has longer duration of action and reduced potential to induce dry mouth, compared with glycopyrrolate. Eur Respir J 2010, 36(Suppl. 54):208s.
69. Fogarty C., Hattersley H., Di Scala L., Drollmann A. Bronchodilatory effects of NVA237, a once daily long-acting muscarinic antagonist, in COPD patients. Respir Med 2011, 105:337-342.
70. Verkindre C., Fukuchi Y., Flemale A., Takeda A., Overend T., Prasad N., et al. Sustained 24-h efficacy of NVA237, a once-daily long-acting muscarinic antagonist, in COPD patients. Respir Med 2010, 104:1482-1489.
71. D'Urzo A., Ferguson G.T., van Noord J.A., Hirata K., Martin C., Horton R., et al. Efficacy and safety of once-daily NVA237 in patients with moderate-to-severe COPD: the GLOW1 trial. Respir Res 2011, 12:156.
72. Kerwin E.M., Hebert J., Pedinoff A., Gallagher N., Martin C., Banjeri D., et al. NVA237 once daily provides rapid and sustained bronchodilation in COPD patients, with efficacy similar to tiotropium: the GLOW2 trial. Am J Respir Crit Care Med 2012, 185:A2920.
73. Korenblat P.E., Hebert J., Gallagher N., Martin C., Banjeri D., Lu Y. NVA237 once daily improves dyspnea and health-related quality of life in patients with COPD: the GLOW2 trial. Am J Respir Crit Care Med 2012, 185:A2254.
74. Kerwin E.M., Pedinoff A., Casale T.B., Gallagher N., Martin C., Banjeri D., et al. NVA237 once daily reduces COPD exacerbations with similar rates to tiotropium: the GLOW2 trial. Am J Respir Crit Care Med 2012, 185:A2255.
75. Beeh K.M., Drollmann A., Di Scala L., Smith R. Once-daily NVA237 improves exercise endurance from first dose in patients with COPD: the GLOW3 trial. Eur Respir J 2011, 38(Suppl. 55):819s.
76. Sechaud R., Renard D., Zhang-Auberson L., Motte S.L., Drollmann A., Kaiser G. Pharmacokinetics of multiple inhaled NVA237 doses in patients with chronic obstructive pulmonary disease (COPD). Int J Clin Pharmacol Ther 2012, 50:118-128.
77. Vogelmeier C., Verkindre C., Cheung D., Galdiz J.B., Guclu S.Z., Spangenthal S., et al. Safety and tolerability of NVA237, a once-daily long-acting muscarinic antagonist, in COPD patients. Pulm Pharmacol Ther 2010, 23:438-444.
78. ® in patients with COPD. Am J Respir Crit Care Med 2010, 181:A4450.
79. Orevillo C., St Rose E., Strom S., Fischer T., Golden M., Thomas M., et al. Glycopyrrolate MDI demonstrates comparable efficacy and safety to tiotropium DPI in a randomised, double-blind, placebo-controlled phase 2b study in patients with COPD. Eur Respir J 2011, 38(Suppl. 55):724s.
80. Singh D., Leaker A., Tutuncu A. Efficacy and safety of nebulized glycopyrrolate (EP-101) for administration using high efficiency nebulizer in patients with COPD. Eur Respir J 2011, 38(Suppl. 55):147s.
81. Lainé D.I., Luttman M.A., Foley J.J., Dehaas C.J., Kotzer C.J., Salmon M., et al. The pre-clinical pharmacology of the inhaled muscarinic antagonist GSK573719 predicts once-daily clinical dosing. Eur Respir J 2011, 38(Suppl 55):613s.
82. Mehta R., Hardes K., Cahn A., Newlands A., Donald A., Preece A., et al. Safety, tolerability and pharmacokinetics (PK) of repeated doses of GSK573719 inhalation powder, a new long-acting muscarinic antagonist in healthy adults. Eur Respir J 2011, 38(Suppl. 55):723s.
83. Cahn A., Lovick R., Newlands A., Deans A., Pouliquen A., Preece A., et al. Safety, tolerability, pharmacodynamics (PD) and pharmacokinetics (PK) of GSK573719 inhalation powder in healthy subjects. Eur Respir J 2011, 38(Suppl. 55):723s.
84. Decramer M., Maltais F., Feldman G., Brooks J., Willits L., Harris S., et al. Dose-related efficacy of GSK573719, a new long-acting muscarinic receptor antagonist (LAMA) offering sustained 24-hour bronchodilation, in COPD. Eur Respir J 2011, 38(Suppl. 55):150s.
85. Donohue J.F., Anzueto A., Brooks J., Mehta R., Kalberg C., Crater G. A randomized, double-blind dose-ranging study of the novel LAMA GSK573719 in patients with COPD. Respir Med 2012, 106:970-979.
86. Kelleher D., Preece A., Mehta R., Donald A., Hardes K., Cahn A., et al. Phase II study of once-daily GSK573719 inhalation powder, a new long-acting muscarinic antagonist, in patients with chronic obstructive pulmonary disease (COPD). Eur Respir J 2011, 38(Suppl. 55):140s.
87. van Noord J.A., Buhl R., Laforce C., Martin C., Jones F., Dolker M., et al. QVA149 demonstrates superior bronchodilation compared with indacaterol or placebo in patients with chronic obstructive pulmonary disease. Thorax 2010, 65:1086-1091.
88. Van de Maele B., Fabbri L.M., Martin C., Horton R., Dolker M., Overend T. Cardiovascular safety of QVA149, a combination of indacaterol and NVA237, in COPD patients. COPD 2010, 7:418-427.
89. Bouyssou T., Casarosa P., Naline E., Pestel S., Konetzki I., Devillier P., et al. Pharmacological characterization of olodaterol, a novel inhaled beta2-adrenoceptor agonist exerting a 24-hour-long duration of action in preclinical models. J Pharmacol Exp Ther 2010, 334:53-62.
90. Smit M., Zuidhof A.B., Bos I.S.T., Maarsingh H., Gosens R., Zaagsma J., et al. The bronchoprotective effect of olodaterol against histamine is synergistically enhanced and prolonged by tiotropium bromide. Am J Respir Crit Care Med 2011, 183:A1379.
91. Smit M., Zuidhof A.B., Bos I.S.T., Maarsingh H., Gosens R., Zaagsma J. Acute reversal of allergan-induced airway hyperresponsiveness (AHR) by olodaterol is synergistically enhanced by tiotropium bromide. Eur Respir J 2011, 38(Suppl. 55):308s.
92. Maltais F., Beck E., Webster D., Maleki-Yazdi M.R., Seibt J.-V., Arnoux A., et al. Four weeks once daily treatment with tiotropium+olodaterol (BI 1744) fixed dose combination compared with tiotropium in COPD patients. Eur Respir J 2010, 36(Suppl. 54):1014s.
93. Marjason J., Orevillo C., St Rose E., Ferguson G.T., Vehring R., Joshi V., et al. Assessment of safety and pharmacokinetic profile of a novel fixed combination of glycopyrrolate and formoterol HFA MDI in healthy volunteers. Am J Respir Crit Care Med 2010, 181:A4455.
94. Reisner C., St Rose E., Strom A., Fischer T., Golden M., Thomas M., et al. Fixed combination of glycopyrrolate and formoterol MDI (GFF-MDI) demonstrates superior inspiratory capacity (IC) compared to tiotropium DPI (Tio) following 7 days dosing, in a randomized, double-blind, placebo controlled phase 2b study in patients with COPD. Eur Respir J 2011, 38(Suppl. 55):150s.
95. Reisner C., Fogarty C., Spangenthal S., Dunn L., Kerwin E.M., Quinn D., et al. Novel combination of glycopyrrolate and formoterol MDI (GFF-MDI) provides superior bronchodilation compared to its components administered alone, tiotropium DPI, and formoterol DPI in a randomized, double-blind, placebo-controlled Phase 2b study in patients with COPD. Am J Respir Crit Care Med 2011, 183:A6435.
96. Reisner C., Rennard S.I., Fogarty C., Fischer T., Rose E.S., Fernades C., et al. Pearl therapeutics' combination LAMA/LABA MDI (GFF-MDI, PT003) provides a significant benefit on home peak expiratory flow rate (PEFR) and reduces the need for rescue Albuterol use compared to its components administered alone, Spiriva(R) Handihaler(R), and Foradil(R) Aerolizer(R) in a randomized, double-blind, placebo-controlled phase 2b study in patients with COPD. Am J Respir Crit Care Med 2012, 185:A2259.
97. Feldman G., Walker R.R., Brooks J., Mehta R., Crater G. Safety and tolerability of the GSK573719/Vilanterol combination in patients with COPD. Am J Respir Crit Care Med 2012, 185:A2938.
98. Norris V., Zhu C.-Q., Ambery C. The pharmcodynamics of GSK961081 in patients with COPD. Eur Respir J 2011, 38(Suppl. 55):138s.
99. Steinfeld T., Hughes A.D., Klein U., Smith J.A., Mammen M. THRX-198321 is a bifunctional muscarinic receptor antagonist and beta2-adrenoceptor agonist (MABA) that binds in a bimodal and multivalent manner. Mol Pharmacol 2011, 79:389-399.
100. 2 adrenoceptor agonist. Eur Respir J 2010, 36(Suppl. 54):218s.
101. Wright K., Clarke N., Yeadon M., Perros-Huguet C. PF-3429281-A novel inhaled dual antimuscarinic/beta2 adrenoceptor agonist in the anaesthetized dog model of bronchoconstriction. Eur Respir J 2010, 36(Suppl. 54):1014s.
102. Patel S., Marshall S., Summerhill S., Strawbridge M., Coghlan M., Strawbridge M., et al. The in-vitro pharmacology of PF-4348235 at recombinant receptors-a novel inhaled dual antimuscarinic/beta2 adrenoceptor agonis. Am J Respir Crit Care Med 2011, 183:A1607.
103. Philip J., Hulland N., Clarke N., Perros-Huguet C., Yeadon M. Demonstration of single and dual pharmacology in vivo of PF-4348235: a novel inhaled dual antimuscarinic/2 agonist. Am J Respir Crit Care Med 2011, 183:A1609.
104. Hulland N., Philip J., Delescluse N., Clarke N., Perros-Huguet C., Yeadon M. Duration of single and dual pharmacology in vivo of PF-4348235: a novel dual antmuscarinic/beta2 agonist in conscious guinea pigs. Am J Respir Crit Care Med 2011, 183:A1610.
105. GOLD Global strategy for the diagnosis, management, and prevention of COPD 2011, [Internet], [cited 2012 May 1]. Available from:. http://www.goldcopd.com.
106. Usmani O.S., Barnes P.J. Assessing and treating small airways disease in asthma and chronic obstructive pulmonary disease. Ann Med 2012, 44:146-156.